DESCRIPTION (as provided by applicant): A major conceptual advance in innate immunity is the discovery of Pathogen Recognition Receptors (PRR), which profoundly shape adaptive immunity to affect host response to pathogens. Major PRRs crucial for innate immunity against viral pathogens include toll-like receptors and RIG-I like receptors, while the role for NLR (nucleotide-binding leucine rich repeat containing, or NOD-like receptor) family in viral infection is just emerging. In this Program, we will focus on the revelation of novel nucleic acid sensing pathways relevant to multiple NIAID priority pathogens. The Program is comprised of three Projects, each led by an international leader in his/her field. The Program will be performed in a highly collaborative fashion with two Cores which will provide cutting edge proteomics and protein purification capabilities, headed by directors who have contributed seminal work in the field of PRRs. The overarching goals are: * To investigate the role of novel PRRs as receptors of viral nucleic acid which affect subsequent innate immune responses to NIAID high priority viral pathogens in human. * To apply cutting edge quantitative proteomic approaches for the identification of novel paradigm-shifting pathways of pathogen sensing. * To contrast and compare role of PRRs across diverse NIAID high priority human viruses. * To reveal cross-talk between multiple PRRs in host response to NIAID priority human viruses * To investigate intracellular trafficking of viral ligands to sites of recognition by PRRs. * To capitalize on unique biochemical capabilities that are technically challenging to quantify the ligand-binding functions of PRRs. * To maximize opportunities for validating experimental findings with primary human materials. These goals are highly response to the RFA-AI-12-048 and are in precise concordance with the stated purpose of the RFA that emphasis of research proposed in response to this FOA should be in defining novel cellular and molecular immune mechanisms involved in immunity to virus infection. It is also responsive because the pathways explored are broadly relevant to multiple high priority pathogens and will be studied in the context of five high priority RNA and DNA viruses. Finally, the proposed work is responsive to the purpose of the RFA because it specifically expands our understanding of novel PRR interaction with viruses and the accompanied changes in signaling pathways by profiling proteomic modifications in human innate immune cells caused by NIAID priority viral pathogens.